Vasopressin (AVP) and angiotensin II (AngII) hormonal systems modulate a variety of physiologic functions affecting multiple organ systems. Of singular importance, is their role in blood pressure regulation. Our long term objective is to dissect the specific contribution of novel AngII and AVP receptors in blood pressure regulation in normal and pathophysiological states. Several isoreceptors for both AngII and AVP have been recently characterized. Of these, the dual AngII/AVP receptor, isolated by us, elucidates novel information providing the bases for new hypotheses and questions. In this research proposal, we will test the following hypotheses: 1) Based on the detected abundance and assignment by immunocytochemical localization of the AngII/AVP receptor polypeptide to renal epithelial cells of the outer medullary thick ascending limb tubules and inner medullary collecting ducts, we hypothesize that the AngII/AVP receptor is a prominent renal physiologic target for AngII and AVP, and therefore plays an important role in salt- water balance and blood pressure regulation; 2) Based on the elucidation of functional significant mutations in the Dahl Salt-Sensitive rat AngII/AVP receptor, we hypothesize that the AngII/AVP receptor is a genetic determinant for salt-sensitive hypertension in the Dahl Salt- Sensitive hypertensive rat. Accordingly, the following specific aims are prioritized: I) Dissection of potential pathophysiologic involvement of the AngII/AVP receptor in hypertension 1A) Assessment of the specific contribution(s) of N119S and C163R substitutions to the increased sensitivity to Ang II and AVP and enhanced Gs-coupling observed in the Dahl S AngII/AVP receptor; 1B) Genetic cosegregation analysis of the AngII/AVP receptor with blood pressure and renal pathology in an F2 (Dahl S male x Dahl R female) cohort comprised of male and female rats in order to determine whether the mutant AngII/AVP receptor cosegregates with high blood pressure and/or with hypertensive renal disease. II) Dissection of physiologic role of the AngII/AVP receptor: 2A) Tissue specific, spatial and temporal expression patterns in development of the AngII/AVP receptor gene, establishing a foundation for assessing its function in an integrated biologic experimental system as in the gene targeting experiments proposed below. 2B) Targeted disruption of the AngII/AVP receptor gene in mice in order to define its physiologic role in an integrated biologic experimental system. These studies will elucidate the physiologic role of the AngII/AVP receptor and will define the status of the AngII/AVP receptor as a candidate hypertension susceptibility gene, thus paving the way for the direct assessment of the mechanistic role of this receptor in salt-sensitive hypertension and its role in the development of hypertension in selective human populations.